Paul Ehrlich, the Rockefeller Institute, and the First Targeted Chemotherapy

Paul Ehrlich (left) and Sahachiro Hata

The German physician Paul Ehrlich (1854-1915) announced in 1910 the
development of an arsenic-based drug called Salvarsan ("the arsenic
that saves") that was effective against syphilis, an important threat
to public health worldwide. It was the first drug methodically
developed to treat a specific disease, and the crowning achievement to
a career that contributed fundamentally to knowledge of immunology,
hematology, chemistry, histology, and pharmacology, and had already
been recognized by a Nobel Prize in 1908.

Ehrlich's interest in finding targeted drugs dated back to
the 1890s when he noticed that synthetic dyes could selectively stain
specific pathogens and not their host cells. He experimented first with
methylene blue as a therapy for malaria. In the early 1900s he studied
the effectiveness of trypan red against the trypanosomes that cause
African sleeping sickness. He next turned to an arsenic compound that
had been tested against trypanosomiasis, and proceeded to determine its
chemical structure and synthesize more than a thousand variations of
it. The spirochete that causes syphilis was discovered in 1906. Soon
after, Ehrlich's student and colleague Sahachiro Hata (1873-1938), who
had succeeded in infecting rabbits with syphilis, joined his
laboratory, and the two scientists set about systematically screening
their collection of arsenic compounds for activity against syphilis,
and testing the results in animals. Compound number 606, arsphenamine,
turned out to be Ehrlich's "magic bullet."

Three entries in Paul Ehrlich's laboratory notebook dated 1906-1912 illustrate the development of Salvarsan 606

During this research, Ehrlich maintained strong ties to the leaders of
the new Rockefeller Institute, founded in 1901. In 1903, Christian
Herter, perhaps the most influential member of the Institute's Board,
spent the year working and observing in Ehrlich's laboratory, and the
two became close friends. Ehrlich also corresponded regularly with
Simon Flexner, the Institute's first director. That was how, in 1909,
Flexner knew that Ehrlich's research was coming under increasing
financial strain. Flexner went directly to John D. Rockefeller to
request support for Ehrlich's work. Rockefeller responded with a gift
of $10,000, which was channeled through the Rockefeller Institute as a
grant to Ehrlich. Ehrlich received notice of this grant in August of
1909, a time when he and Hata were in the midst of screening their
arsenic-based compounds. That fall, when compound number 606 was found
to be effective, they tested it in animals for safety, and then in
patients with primary syphilis. In April of 1910 they announced their
results at the Congress for Internal Medicine at Wiesbaden.

Salvarsan was the most effective syphilis treatment
available, and Hoechst began manufacturing the drug in 1910. But it was
difficult, and sometimes risky, to administer. Ehrlich continued to
refine the compound, and announced the synthesis of Neosalvarsan
(neoarsphenamine), which was more soluble in water, in 1914. In the
meantime, the Rockefeller Hospital was one of the first recipients of
the 65,000 free samples of Salvarsan that Ehrlich distributed, free of
charge, so that further clinical testing could be done. At Rockefeller,
Homer F. Swift (1881-1953) developed a safe and successful method to
use Salvarsan in treating the dementia and paralysis of late-stage
syphilis. By 1923, 2 million doses a year of Salvarsan and Neosalvarsan
were being manufactured in the United States, and these drugs remained
in use until the introduction of penicillin in the 1940s.

The researcher's office, a repository for journals, books, and papers of every kind

Paul Ehrlich was educated at the universities of Breslau, Strassburg,
and Freiburg, and received his medical degree from the University of
Leipzig in 1878. After research at the Charité Hospital in Berlin,
Ehrlich joined the faculty of the University of Berlin in 1882. In 1890
he was invited to work at the Koch Institute, where he developed
methods to produce high-grade sera against diphtheria and other toxins.
In 1899 the Institute for Serum Research and Serum Testing was
established for Ehrlich outside Berlin. In 1906, Ehrlich became the
first head of the newly established Georg-Speyer-Haus, a research
institute for chemotherapy. Ehrlich was a member of some 81
international academies and learned societies, and the recipient of ten
honorary degrees. In addition to the 1908 Nobel Prize, shared with Ilya
Illyich Mechnikov, he received the Prussian Great Gold Medal for
Science (1903), was named full honorary professor of the University of
Gottingen (1904), and was appointed Privy Councillor to the government
of Prussia (1911).